Penicillin and cephalosporin biosynthesis: Mechanism of carbon catabolite regulation of penicillin production

Penicillins and cephalosporins are synthesized by a series of enzymatic rea ctions that form the tripeptide delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-v aline and convert this tripeptide into the final penicillin or cephalospori n molecules. One of the enzymes, isopenicillin N synthase has been crystall yzed and its active center identified. The three genes pcbAB, pcbC and penD E involved in penicillin biosynthesis are clustered in Penicillium chrysoge num, Aspergillus nidulans and Penicillium nalgiovense. Carbon catabolite re gulation of penicillin biosynthesis is exerted by glucose and other easily utilizable carbon sources but not by lactose. The glucose effect is enhance d by high phosphate concentrations. Glucose represses the biosynthesis of p enicillin by preventing the formation of the penicillin biosynthesis enzyme s. Transcription of the pcbAB, pcbC and penDE genes of P. chrysogenum is st rongly repressed by glucose and the repression is not reversed by alkaline pHs. Carbon catabolite repression of penicillin biosynthesis in A. nidulans is not mediated by CreA and the same appears to be true in P. chrysogenum. The first two genes of the penicillin pathway (pcbAB and pcbC) are express ed from a bidirectional promoter region. Analysis of different DNA fragment s of this bidirectional promoter region revealed two important DNA sequence s (boxes A and B) for expression and glucose catabolite regulation of the p cbAB gene. Using protein extracts from mycelia grown under carbon catabolit e repressing or derepressing conditions DNA-binding proteins that interact with the bidirectional promoter region were purified to near homogeneity.